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Subnanometer Pt Catalysts Encapsulated in MEL Zeolite Mesocrystals for H₂ Production from Methylcyclohexane Dehydrogenation

Enhanced Nanoconfinement of Copper-Organic Interfaces within Phthalocyanine Frameworks for Selective Electroreduction of CO to Acetate

Inhibition of Rho-Associated Kinases ROCK1 and ROCK2 as a Therapeutic Strategy to Reactivate the Repressed <i>FXN</i> Gene in Friedreich Ataxia

Friedreich ataxia (FA) is an autosomal recessive disease characterized by progressive damage to the nervous system and severe cardiac abnormalities. The disease is caused by a GAA•TTC triplet repeat expansion in the first intron of the FXN gene, resulting in epigenetic repression of FXN transcription and reduction in FXN (frataxin) protein which results in mitochondrial dysfunction. Factors and pathways that promote FXN repression represent potential therapeutic targets whose inhibition would restore FXN transcription and frataxin protein levels. Here, we performed a candidate-based RNAi screen to identify kinases, a highly druggable class of proteins, that when knocked down upregulate FXN expression. Using this approach, we identified Rho kinase ROCK1 as a critical factor required for FXN repression. ShRNA-mediated knockdown of ROCK1, or the related kinase ROCK2, increases FXN mRNA and frataxin protein levels in FA patient-derived induced pluripotent stem cells (iPSCs) and differentiated neurons and cardiomyocytes to levels observed in normal cells. We demonstrate that small molecule ROCK inhibitors, including the FDA-approved drug belumosudil and fasudil, reactivate FXN expression in cultured FA iPSCs, neurons, cardiomyocytes, and FA patient primary fibroblasts and ameliorate the characteristic mitochondrial defects in these cell types. Remarkably, treatment of transgenic FA mice of both sexes with belumosudil or fasudil upregulates FXN expression, ameliorates the mitochondrial defects in the brain and heart tissues, and improves motor coordination and muscle strength. Collectively, our study identifies ROCK kinases as critical repressors of FXN expression and provides preclinical evidence that FDA-approved ROCK inhibitors may be repurposed for treatment of FA.

Keteniminium-Mediated Postpolymerization Modification: Unlocking Emergent Properties in Polyacrylamides

Open-Shell Species Enabled Diverse Deoxygenative Cyanofunctionalization of Aldehydes under Metal-Free Conditions

Turing-Patterned Catalyst-Ionomer Architectures for Enhanced Mass Transport in Anion Exchange Membrane Fuel Cells

Assembling a Metastable Electron Fence within Gold-Zeolite Interfaces for Boosted Propylene Epoxidation

Microglia Support Both the Singular Form of LTP Expressed by the Lateral Perforant Path and Episodic Memory

We report here that microglia exert a surprisingly discrete but functionally critical influence on synaptic plasticity in the mouse hippocampus. Treatment of adult male mice with colony-stimulating factor 1 receptor antagonist PLX5622 (PLX), with resultant depletion of forebrain microglia, did not disturb basal synaptic transmission at four synaptic connections in the hippocampus. Long-term potentiation (LTP) was also intact for three of these sites, but the singular, endocannabinoid-dependent form of LTP expressed by lateral perforant path (LPP) input to the dentate gyrus (DG) was severely impaired. The LPP–LTP defect occurred in conjunction with a pronounced increase in DG (but not neocortical) levels of 2-arachidonoylglycerol (2-AG), the retrograde (spine-to-terminal) endocannabinoid messenger that initiates LPP–LTP. Despite this, concentrations of the 2-AG synthetic enzyme diacylglycerol lipase were not affected by PLX treatment. Synaptic levels of the cannabinoid type 1 receptor, which mediates 2-AG effects on LPP–LTP, were similarly unaffected. Prior work has implicated the LPP in episodic memory. We determined that the LPP–LTP impairment in PLX-treated mice was accompanied by a failure to acquire the three basic elements of an episode: the identities, locations, and presentation order for a collection of olfactory cues. Treatment with JZL184, which inhibits the 2-AG degradative enzyme monoglyceride lipase, restored both LPP–LTP and episodic “What” encoding in PLX-treated mice. We conclude that microglia selectively regulate endocannabinoid transmission at the LPP→DG synapse and thereby potently influence synaptic plasticity at the initial stage of a corticohippocampal circuit that is critical for episodic memory.

Combining Theory and Experiment to Map the Atomic-Level Structure–Energy Pathways of Adsorbate-Mediated Phase Changes in a Cooperatively Flexible Metal–Organic Framework

Selective Mass Accumulation at the Metal–Polymer Bridging Interface for Efficient Nitrate Electroreduction to Ammonia and Zn-Nitrate Batteries

Wavelength-Orthogonal Optodynamics to Overcome the Statistical Limitations of Interfacial Photopolymerizations

Proton-Transfer Kinetics at Liquid–Liquid Interfaces

Description of the Electronic Structure of Oxyhemoglobin Using Fe L-Edge X-ray Absorption Spectroscopy

Asparaginyl Ligases with Engineered Substrate Specificity for Controlled, Sequential Transpeptidation Reactions

Modulation of Dopamine Neurons Alters Behavior and Event Encoding in the Nucleus Accumbens during Pavlovian Conditioning

When a cue is located away from its associated reward, some animals will learn to approach the site of reward (goal-tracking behavior) while others will approach the cue (sign-tracking behavior). The acquisition of sign tracking, but not goal tracking, is dependent on dopamine in the nucleus accumbens (NAc), and we have previously demonstrated that reward-evoked activity in the NAc core may reflect different patterns of dopamine release in sign tracker versus goal tracker individuals. However, a causal relationship among dopamine release, NAc activity, and sign tracking has not been established. Using male and female TH::Cre rats, we expressed inhibitory or excitatory opsins in dopamine neurons of the ventral tegmental area (VTA) and examined the impact of optical manipulation of dopamine neurons on behavior and concurrent NAc neuronal activity. We found that inhibition of VTA dopamine neurons at the time of reward suppressed the acquisition of sign-tracking, but not goal-tracking, behavior. On the other hand, stimulation of dopamine neurons did not alter the acquisition of sign tracking; however, cessation of stimulation impeded further acquisition of sign tracking. Finally, both inhibition and stimulation of VTA dopamine neurons rapidly modulated activity in a subset of NAc neurons and led to changes in cue- and reward-related activity across sessions. Overall, these findings support the ideas that sign tracking and goal tracking are the products of two different learning processes—one dopamine-dependent and one not—and that the impact of VTA dopamine on sign tracking may be mediated by activity in the NAc core.

Pathway to P(V)-Stereogenic Phosphoramidates by Enantioselective Yttrium Catalysis

Unlocking the Ambiphilicity of the Boryl Anion: Synthesis and Reactivity of an Anionic Diazoborane

Anchoring Functional Connectivity to Individual Sulcal Morphology Yields Insights in a Pediatric Study of Reasoning

A salient neuroanatomical feature of the human brain is its pronounced cortical folding, and there is mounting evidence that sulcal morphology is relevant to functional brain architecture and cognition. However, the relationships between sulcal anatomy, brain activity, and behavior are still poorly understood. We previously found that the depth of three small, shallow sulci in the lateral prefrontal cortex (LPFC) was linked to reasoning performance during development (Voorhies et al., 2021). These findings beg the question: What is the linking mechanism between sulcal morphology and cognition? Here, we investigated functional connectivity among sulci in LPFC and the lateral parietal cortex in participants drawn from the same sample as our previous study. We leveraged manual parcellations (21 sulci/hemisphere, 1,806 total) and functional magnetic resonance imaging data from a reasoning task from 43 participants aged 7–18 years (20 females). We conducted clustering and classification analyses of individual-level functional connectivity among sulci. Broadly, we found that (1) connectivity patterns of individual sulci could be differentiated and more accurately than cortical patches equated for size and shape; (2) sulcal connectivity did not consistently correspond with that of probabilistic labels or large-scale networks; (3) sulci clustered based on connectivity patterns, not dictated by spatial proximity; and (4) across individuals, greater depth was associated with higher network centrality for several sulci under investigation. These results illustrate how sulcal morphology can be functionally relevant and provide proof of concept that using sulci to define an individual coordinate space for functional connectomes is a promising future direction.

Investigation of Americium-Containing Phosphates, Silicates, Borates, Molybdates, and Fluorides Synthesized via High-Temperature Flux Crystal Growth

Linear Anion Chain-Assembled Nonporous Swelling Molecular Sieve for Benchmark C2–C4 Hydrocarbon Separations